We hypothesize that inflammatory stimuli including cytokines, growth factors and vasoactive peptides induce prostaglandin endoperoxide synthase 2 (PGHS-2) leading to enhanced formation of biologically actiVe eicosanoids in glomerular mesangial cells in vitro and in vivo. We believe that PGHS-2-derived eicosanoids including PGE2, PGF2alpha, and TxA2 induce chronic alterations of glomerular mesangial cells through stimulation of cellular proliferation and/or enhancement of matrix synthesis. We propose in vitro and in vivo experiments to test this hypothesis. Specific Aim 1 describes experiments to assess the regulation of PGHS-2, in response to inflammatory stimuli, with cultured rat glomerular mesangial cells. We will evaluate the transcriptional, translational and post-translational effects of cytokines (IL-1 beta), growth factors (EGF and basic FGF), and constrictor peptides (ET-I) on PGHS-2 mRNA, protein and cyclooxy-genase activity. We will also test our theory that these stimuli activate kinases which phosphorylate and activate proteins regulating PGHS-2 expression and also phosphorylate PGHS-2 thereby enhancing its cyclo-oxygenase activity. We will correlate the effects of these agonists on PGHS-2-induced eicosanoid synthesis and mesangial proliferation and matrix secretion. In Specific Aim 2, we propose experiments to inhibit the transcriptional, translational or post-translational activation of PGHS-2 using dexamethasone, heparin, antisense strategies or specific nonsteroidal inhibitors of the enzyme. We anticipate that inhibition of the expression or activity of PGHS-2 with subsequent reduction of eicosanoid synthesis will attenuate the mitogenic and matrix stimulatory actions of these inflammatory agonists. In Specific Aim 3, we propose in vivo experiments using experimental models of glomerulosclerosis and rapidly progressive glomerulo-nephritis in the rat. We will correlate the induction of PGHS-2 mRNA and protein in the kidney and the renal synthesis of eicosanoids with the evolution of the glomerulosclerosis or the crescentic glomerulo-nephritis. Furthermore, we will evaluate the therapeutic efficacy of dexamethasone, heparin and selective nonsteroidal inhibitors of PGHS-2 on the expression or activity of PGHS-2 in the kidney. We will then correlate the reductions of eicosanoid synthesis with the beneficial actions of therapy to reduce progressive glomerulosclerosis or progressive crescentic glomerulonephritis. An integrated assessment of these in vitro and in vivo experiments should allow us to confirm or reject our hypothesis that PGHS-2 constitutes an important common pathway mediating glomerulosclerosis and glomerulonephritis.